Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Leora Witkowski; Jian Carrot-Zhang; Steffen Albrecht; Somayyeh Fahiminiya; Nancy Hamel; Eva Tomiak; David Grynspan; Emmanouil Saloustros; Javad Nadaf; Barbara Rivera; Catherine Gilpin; Ester Castellsagué; Rachel Silva-Smith; François Plourde; Mona Wu; Avi Saskin; Madeleine Arseneault; Rouzan G. Karabakhtsian; Elizabeth A. Reilly; Frederick R. Ueland; Anna Margiolaki; Kitty Pavlakis; Sharon M. Castellino; Janez Lamovec; Helen J. Mackay; Lawrence M. Roth; Thomas M. Ulbright; Tracey A. Bender; Vassilis Georgoulias; Michel Longy; Andrew Berchuck; Marc Tischkowitz; Inga Nagel; Reiner Siebert; Colin J.R. Stewart; Jocelyne Arseneau; W. Glenn McCluggage; Blaise A. Clarke; Yasser Riazalhosseini; Martin Hasselblatt; Jacek Majewski; William D. Foulkes

doi:10.1038/ng.2931

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Leora Witkowski, Jian Carrot-Zhang, Steffen Albrecht, Somayyeh Fahiminiya, Nancy Hamel, Eva Tomiak, David Grynspan, Emmanouil Saloustros, Javad Nadaf, Barbara Rivera, Catherine Gilpin, Ester Castellsagué, Rachel Silva-Smith, François Plourde, Mona Wu, Avi Saskin, Madeleine Arseneault, Rouzan G. Karabakhtsian, Elizabeth A. Reilly, Frederick R. UelandAnna Margiolaki, Kitty Pavlakis, Sharon M. Castellino, Janez Lamovec, Helen J. Mackay, Lawrence M. Roth, Thomas M. Ulbright, Tracey A. Bender, Vassilis Georgoulias, Michel Longy, Andrew Berchuck, Marc Tischkowitz, Inga Nagel, Reiner Siebert, Colin J.R. Stewart, Jocelyne Arseneau, W. Glenn McCluggage, Blaise A. Clarke, Yasser Riazalhosseini, Martin Hasselblatt, Jacek Majewski, William D. Foulkes

Research output: Contribution to journal › Article › peer-review

357 Scopus citations

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Original language	English
Pages (from-to)	438-443
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	5
DOIs	https://doi.org/10.1038/ng.2931
State	Published - May 2014

Bibliographical note

Funding Information:
This work is dedicated to the memory of Georgia Enter and Latosha Durham. We thank K. Hill and the Small Cell Ovarian Cancer Foundation for help in recruitment to this study, B. Vanderhyden (University of Ottawa) for providing the BIN-67 cells, S. Croce and C.S. Choong for aiding in the collection of pathological samples, P.-O. Fiset for help with immunohistochemistry and N. Benlimame, R. Zühlke-Jenisch, C. Kemming, M. Leiße, S. Peetz-Dienhart, L. Raestrup, K. Schmidt and C. Theile for technical assistance. N. Jabado, I. Bah and members of the Foulkes laboratory provided helpful discussions. We also thank the McGill University and Génome Québec Innovation Centre for their cooperation, H. Pierce for her help with contacting family 1 and D. Samelak for her help with family 3. Equipment for immunohistochemistry analysis was made available through Sonderforschungsbereich Transregio (SFB TR) 128 (grant to T. Kuhlmann (Z1)). We received funding from the Jewish General Hospital Foundation and the Jodi Taiger Lazarus Fund (W.D.F.), the Fonds de Recherche du Québec–Santé (L.W.), KinderKrebsInitiative Buchholz/Holm-Seppensen (R.S.) and Interdisziplinären Zentrum für Klinische Forschung (IZKF) Münster (Ha3/016/11) (M.H.).

Funding

This work is dedicated to the memory of Georgia Enter and Latosha Durham. We thank K. Hill and the Small Cell Ovarian Cancer Foundation for help in recruitment to this study, B. Vanderhyden (University of Ottawa) for providing the BIN-67 cells, S. Croce and C.S. Choong for aiding in the collection of pathological samples, P.-O. Fiset for help with immunohistochemistry and N. Benlimame, R. Zühlke-Jenisch, C. Kemming, M. Leiße, S. Peetz-Dienhart, L. Raestrup, K. Schmidt and C. Theile for technical assistance. N. Jabado, I. Bah and members of the Foulkes laboratory provided helpful discussions. We also thank the McGill University and Génome Québec Innovation Centre for their cooperation, H. Pierce for her help with contacting family 1 and D. Samelak for her help with family 3. Equipment for immunohistochemistry analysis was made available through Sonderforschungsbereich Transregio (SFB TR) 128 (grant to T. Kuhlmann (Z1)). We received funding from the Jewish General Hospital Foundation and the Jodi Taiger Lazarus Fund (W.D.F.), the Fonds de Recherche du Québec–Santé (L.W.), KinderKrebsInitiative Buchholz/Holm-Seppensen (R.S.) and Interdisziplinären Zentrum für Klinische Forschung (IZKF) Münster (Ha3/016/11) (M.H.).

Funders	Funder number
Interdisziplinären Zentrum für Klinische Forschung	Ha3/016/11
Jodi Taiger Lazarus Fund
KinderKrebsInitiative Buchholz/Holm-Seppensen
Fonds de Recherche du Québec-Santé
Jewish General Hospital

ASJC Scopus subject areas

Genetics

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10.1038/ng.2931

Cite this

Witkowski, L., Carrot-Zhang, J., Albrecht, S., Fahiminiya, S., Hamel, N., Tomiak, E., Grynspan, D., Saloustros, E., Nadaf, J., Rivera, B., Gilpin, C., Castellsagué, E., Silva-Smith, R., Plourde, F., Wu, M., Saskin, A., Arseneault, M., Karabakhtsian, R. G., Reilly, E. A., ... Foulkes, W. D. (2014). Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nature Genetics, 46(5), 438-443. https://doi.org/10.1038/ng.2931

@article{add949f8bb2648f8a890f990b5efe1bf,

title = "Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type",

abstract = "Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.",

author = "Leora Witkowski and Jian Carrot-Zhang and Steffen Albrecht and Somayyeh Fahiminiya and Nancy Hamel and Eva Tomiak and David Grynspan and Emmanouil Saloustros and Javad Nadaf and Barbara Rivera and Catherine Gilpin and Ester Castellsagu{\'e} and Rachel Silva-Smith and Fran{\c c}ois Plourde and Mona Wu and Avi Saskin and Madeleine Arseneault and Karabakhtsian, {Rouzan G.} and Reilly, {Elizabeth A.} and Ueland, {Frederick R.} and Anna Margiolaki and Kitty Pavlakis and Castellino, {Sharon M.} and Janez Lamovec and Mackay, {Helen J.} and Roth, {Lawrence M.} and Ulbright, {Thomas M.} and Bender, {Tracey A.} and Vassilis Georgoulias and Michel Longy and Andrew Berchuck and Marc Tischkowitz and Inga Nagel and Reiner Siebert and Stewart, {Colin J.R.} and Jocelyne Arseneau and McCluggage, {W. Glenn} and Clarke, {Blaise A.} and Yasser Riazalhosseini and Martin Hasselblatt and Jacek Majewski and Foulkes, {William D.}",

note = "Funding Information: This work is dedicated to the memory of Georgia Enter and Latosha Durham. We thank K. Hill and the Small Cell Ovarian Cancer Foundation for help in recruitment to this study, B. Vanderhyden (University of Ottawa) for providing the BIN-67 cells, S. Croce and C.S. Choong for aiding in the collection of pathological samples, P.-O. Fiset for help with immunohistochemistry and N. Benlimame, R. Z{\"u}hlke-Jenisch, C. Kemming, M. Lei{\ss}e, S. Peetz-Dienhart, L. Raestrup, K. Schmidt and C. Theile for technical assistance. N. Jabado, I. Bah and members of the Foulkes laboratory provided helpful discussions. We also thank the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre for their cooperation, H. Pierce for her help with contacting family 1 and D. Samelak for her help with family 3. Equipment for immunohistochemistry analysis was made available through Sonderforschungsbereich Transregio (SFB TR) 128 (grant to T. Kuhlmann (Z1)). We received funding from the Jewish General Hospital Foundation and the Jodi Taiger Lazarus Fund (W.D.F.), the Fonds de Recherche du Qu{\'e}bec–Sant{\'e} (L.W.), KinderKrebsInitiative Buchholz/Holm-Seppensen (R.S.) and Interdisziplin{\"a}ren Zentrum f{\"u}r Klinische Forschung (IZKF) M{\"u}nster (Ha3/016/11) (M.H.).",

year = "2014",

month = may,

doi = "10.1038/ng.2931",

language = "English",

volume = "46",

pages = "438--443",

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Witkowski, L, Carrot-Zhang, J, Albrecht, S, Fahiminiya, S, Hamel, N, Tomiak, E, Grynspan, D, Saloustros, E, Nadaf, J, Rivera, B, Gilpin, C, Castellsagué, E, Silva-Smith, R, Plourde, F, Wu, M, Saskin, A, Arseneault, M, Karabakhtsian, RG, Reilly, EA, Ueland, FR, Margiolaki, A, Pavlakis, K, Castellino, SM, Lamovec, J, Mackay, HJ, Roth, LM, Ulbright, TM, Bender, TA, Georgoulias, V, Longy, M, Berchuck, A, Tischkowitz, M, Nagel, I, Siebert, R, Stewart, CJR, Arseneau, J, McCluggage, WG, Clarke, BA, Riazalhosseini, Y, Hasselblatt, M, Majewski, J & Foulkes, WD 2014, 'Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type', Nature Genetics, vol. 46, no. 5, pp. 438-443. https://doi.org/10.1038/ng.2931

TY - JOUR

T1 - Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

AU - Witkowski, Leora

AU - Carrot-Zhang, Jian

AU - Albrecht, Steffen

AU - Fahiminiya, Somayyeh

AU - Hamel, Nancy

AU - Tomiak, Eva

AU - Grynspan, David

AU - Saloustros, Emmanouil

AU - Nadaf, Javad

AU - Rivera, Barbara

AU - Gilpin, Catherine

AU - Castellsagué, Ester

AU - Silva-Smith, Rachel

AU - Plourde, François

AU - Wu, Mona

AU - Saskin, Avi

AU - Arseneault, Madeleine

AU - Karabakhtsian, Rouzan G.

AU - Reilly, Elizabeth A.

AU - Ueland, Frederick R.

AU - Margiolaki, Anna

AU - Pavlakis, Kitty

AU - Castellino, Sharon M.

AU - Lamovec, Janez

AU - Mackay, Helen J.

AU - Roth, Lawrence M.

AU - Ulbright, Thomas M.

AU - Bender, Tracey A.

AU - Georgoulias, Vassilis

AU - Longy, Michel

AU - Berchuck, Andrew

AU - Tischkowitz, Marc

AU - Nagel, Inga

AU - Siebert, Reiner

AU - Stewart, Colin J.R.

AU - Arseneau, Jocelyne

AU - McCluggage, W. Glenn

AU - Clarke, Blaise A.

AU - Riazalhosseini, Yasser

AU - Hasselblatt, Martin

AU - Majewski, Jacek

AU - Foulkes, William D.

N1 - Funding Information: This work is dedicated to the memory of Georgia Enter and Latosha Durham. We thank K. Hill and the Small Cell Ovarian Cancer Foundation for help in recruitment to this study, B. Vanderhyden (University of Ottawa) for providing the BIN-67 cells, S. Croce and C.S. Choong for aiding in the collection of pathological samples, P.-O. Fiset for help with immunohistochemistry and N. Benlimame, R. Zühlke-Jenisch, C. Kemming, M. Leiße, S. Peetz-Dienhart, L. Raestrup, K. Schmidt and C. Theile for technical assistance. N. Jabado, I. Bah and members of the Foulkes laboratory provided helpful discussions. We also thank the McGill University and Génome Québec Innovation Centre for their cooperation, H. Pierce for her help with contacting family 1 and D. Samelak for her help with family 3. Equipment for immunohistochemistry analysis was made available through Sonderforschungsbereich Transregio (SFB TR) 128 (grant to T. Kuhlmann (Z1)). We received funding from the Jewish General Hospital Foundation and the Jodi Taiger Lazarus Fund (W.D.F.), the Fonds de Recherche du Québec–Santé (L.W.), KinderKrebsInitiative Buchholz/Holm-Seppensen (R.S.) and Interdisziplinären Zentrum für Klinische Forschung (IZKF) Münster (Ha3/016/11) (M.H.).

PY - 2014/5

Y1 - 2014/5

N2 - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

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ER -

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Abstract

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